Abstract

Objective: Suppression of Kinesin-1 by antisense oligonucleotides, or overexpression of dominant-negative acting kinesin heavy chain (KHC), has been reported to affect the sustained phase of glucose-stimulated insulin secretion in β-cells in vitro. In this study, we examined the in vivo physiological role of Kinesin-1in β-cell development and function.

Research Design and Methods: A Cre-LoxP strategy was used to generate conditional knockout mice in which the Kif5b gene is specifically inactivated in pancreatic β-cells. Physiological and histological analyses were carried out in Kif5b knockout mice as well as littermate controls.

Results: Mice with β-cell specific deletion of Kif5b (Kif5bfl/−:RIP2-Cre) displayed significantly retarded growth as well as slight hyperglycemia in both non-fasting and 16 hr fasting conditions compared to control littermates. In addition, Kif5bfl/−:RIP2-Cre mice displayed significant glucose intolerance, which was not due to insulin resistance but related to an insulin secretory defect in response to glucose challenge. These defects of β-cell function in mutant mice were not coupled with observable changes in islet morphology, islet cell composition or β-cell size. However, compared to controls, pancreas of Kif5bfl/−:RIP2-Cre mice exhibited both reduced islet size and increased islet number, concomitant with an increased insulin vesicle density in β-cells.

Conclusions: In addition to being essential for maintaining glucose homeostasis and regulating β-cell function, Kif5b may be involved in β-cell development by regulating β-cell proliferation and insulin vesicle synthesis.